Current medical and surgical approaches are expensive and are associated with a variety of side effects that may compromise the patient's quality of life. The development of a non-drug, non-surgical therapeutic approach to improve motor function would provide an attractive adjunct to current PD treatment approaches. Animal studies have shown that forced-exercise improves motor function and has neuroprotective qualities. We hypothesize that the apparent contradictory results between human and animal experiments is the result of differences in the exercise paradigms used. The human experiments utilized voluntary whereas forced- exercise was used in animals. Models of PD provide a theoretical framework and rationale for the use of a forced-exercise intervention for PD patients. Decreased motor activation may limit PD patients'ability to generate voluntary movements at rates necessary, based on animal studies, to improve global motor functioning. We developed a safe lower extremity forced-exercise paradigm to augment the voluntary movements of PD patients to assist them in safely achieving an exercise rate greater than their voluntary rate. The results of our R21 project indicate that patients completing an 8-week forced-exercise intervention exhibit a 25% improvement in clinical motor rating scores whereas patients completing a voluntary exercise intervention, of similar aerobic intensity, exhibited no improvements in clinical ratings. Our recent fMRI data indicate that forced-exercise in PD patients produces a similar subcortical and cortical pattern of activation as is seen following administration of levodopa. Global improvements in motor function and increased neural activity suggest forced-exercise may be altering brain function in PD patients. The goal of this project is to determine and compare the effects of forced versus voluntary exercise on PD motor and non-motor function and associated changes in the pattern of neural activity. We propose to conduct a single-center, parallel-group, case-controlled, rater-blinded study. This project will be a continuation of our effort to directly compare the effects of forced and voluntary exercise on motor and non-motor function using clinical and objective biomechanical outcomes in human PD patients. A total of 100 mild to moderate idiopathic PD patients will be randomized to a voluntary, forced or no-exercise control group. Clinical and biomechanical assessments will be performed at five time points: Baseline, mid-treatment, end of treatment (EOT), EOT + 4 and EOT + 8 weeks. It is hypothesized that patients completing forced-exercise will exhibit a global improvement in motor function and reduced non-motor symptoms compared to the voluntary and no-exercise groups. If forced- exercise is shown effective, it could become a viable alternative or adjunct therapy to pharmacologic or surgical approaches. The proposed cycling intervention is simple, can be self-directed, is relatively inexpensive (~$2,500 for a consumer version) and could immediately be translated to an inpatient or outpatient clinical setting or a patient's home. PUBLIC HEALTH RELEVANCE: Current medical and surgical approaches to Parkinson's disease (PD) are expensive and associated with a variety of side effects that may compromise the patient's quality of life. Development of a non-drug, non- surgical therapeutic approach to improve motor and non-motor function would provide an attractive adjunct to current PD treatment approaches. Our recent results indicate that an 8-week forced-exercise intervention improve global motor function as compared to voluntary exercise. We propose to determine and compare the effects of forced and voluntary exercise on PD motor and non-motor function using an intervention developed in our ongoing R21 project. Identifying the specific relationship between exercise interventions and motor/non- motor function in PD will provide as basis for PD specific exercise recommendations.